Calcineurin is a phosphatase which is activated depending on calcium and calmodulin. It is a complex consisting of calcineurin subunit A (CaNA) having a catalytic center and calcineurin subunit B (CaNB) being a regulating factor. Calcineurin usually exists in an unactive form in the cell, because the association of the catalytic center with a substrate is obstructed by the autoinhibitory domain. The increased intracellular concentration of calcium leads to open the autoinhibitory domain by changing the structure of calcineurin (active form) which results in that the substrate can be associated with the catalytic center. Meanwhile, the decreased intracellular concentration of calcium leads calcineurin to return to the unactive form again. As just described, it is known in the prior art that calcineurin is reversibly activated depending on the concentration of calcium.
In 1999, it was reported that calcineurin played an important role in neuronal cell death (refer to Asai Akio, et al., J. Biological Chemistry, Vol. 274. p. 34450, 1999). Furthermore, it has been also reported that the calcineurin-specific inhibitor (immunosuppressants; FK506 and cyclosporin A) suppresses neuronal cell death (refer to Morioka Motohiro, et al., Progress in Neurobiology, Vol. 58, p. 1, 1999; and Springer Joe E., et al., The Journal of Neuroscience, Vol. 20, p. 7246, 2000). On the basis of many reports including such literatures, as a mechanism of neuronal cell death observed in brain ischmia and spinal injury, it has been suggested now that N-methyl-D-asparginic acid receptor (NMDA receptor), which is one of the glutamic acid receptors, is abnormally activated by the excitation of the neuronal cell followed by an influx of large quantity of calcium into the cell through the receptor, and thereby calcineurin is activated to induce cell death. However, since the influx of calcium is transient, the activated state of calcineurin does not continue for a long term. Therefore, although it is imaged that there is any other mechanism by which calcineurin is activated for the long term than the transient increase of intracellular concentration of calcium, such mechanism has never been reported.
As mentioned above, it is known that immunosuppressants FK506 and cyclosporine A have a suppressive effect on neuronal cell death, in particular ischemic and excitatory neuronal cell death. However, it is known that the side effect of such agents is large (for example, toxicity, diabetes and the like), because the agents suppress all signal transduction involved in calcineurin. Therefore, a suppressant for neuronal cell death which can inhibit a long term activation of calcineurin and show less side effect compared with the conventional one is strongly desired.